Chapter 26

Enzymes that bind phosphoribosyl-5-phosphate (PRPP) have a common structural fold, the PRT fold, which unites them as a structural family. PRT here refers to the phosphoribosyl transferase activity displayed by some family members. Typically, in such reactions, \(\mathrm{PP}_{\mathrm{i}}\) is displaced from PRPP by a nitrogen-containing nucleophile. Several such reactions occur in purine metabolism. Identify two such reactions where the enzyme involved is likely to be a PRT family member.

The crystal structure of \(E\). coli dihydrofolate reductase (DFR) with NADP \(^{+}\) and folate bound can be found in the Protein Data Bank (www.rcsb.org/pdb) as file 7 DFR. Go to this website, enter "7DFR" in the search line, and click on "KiNG" under "Display options" when the 7 DFR page comes up. Explore the KiNG graphic of the DFR structure to visualize how its substrates are bound. (If you hold down the left button on your mouse and move the cursor over the image, you can rotate the structure to view it from different perspectives.) Note in particular the spatial relationship between the nicotinamide ring of \(\mathrm{NADP}^{+}\) and the pterin ring of folate. Do you now have a better appreciation for how this enzyme works? Note also the location of polar groups on the two substrates in relation to the DFR structure.